A new study in animals suggests that targeting antidepressant medications to cells in the gut could not only be an effective treatment of mood disorders like depression and anxiety but may also cause fewer cognitive, gastrointestinal, and behavioral side effects for patients and their children than current treatments.

“Antidepressants like Prozac and Zoloft that raise serotonin levels are important first-line treatments and help many patients but can sometimes cause side effects that patients can’t tolerate. Our study suggests that restricting the drugs to interact only with intestinal cells could avoid these issues,” says Mark Ansorge, associate professor of clinical neurobiology at Columbia University Vagelos College of Physicians and Surgeons, who co-led the study with Kara Margolis, Director of the NYU Pain Research Center and an associate professor of molecular pathobiology in the NYU College of Dentistry.

For pregnant mothers, antidepressants that raise serotonin (called selective serotonin reuptake inhibitors, or SSRIs) present a unique problem, because the drugs cross the placenta and have been associated with mood, cognitive, and gastrointestinal problems later in childhood.

“But not treating a pregnant person’s depression also comes with risks to their children,” Ansorge says. “An SSRI that selectively raises serotonin in the intestine could be a better alternative.”

How do SSRI antidepressants work?

For more than 30 years, SSRIs have been the first-line pharmacological treatments for anxiety and depression. They are also commonly prescribed to treat gastrointestinal issues that co-occur with these mood disorders.

SSRIs boost serotonin signaling, and the drug’s effects on mood are thought to stem from increased serotonin signaling in the brain, where serotonin helps to relay messages.

Serotonin is also produced outside the brain, largely in cells that line the intestines. “In fact, 90% of our bodies’ serotonin is in the gut,” says Margolis, who is also an associate professor of pediatrics and cell biology at NYU Grossman School of Medicine. SSRIs therefore increase serotonin signaling not just in the brain but also in the gut, raising the possibility that increasing serotonin signaling in the gut may impact gut-brain communication and ultimately mood.

The researchers tested this possibility in mice using a combination of genetic engineering, surgery, and pharmaceuticals.

Increasing intestinal serotonin reduces anxiety, depressive behaviors in mice

To determine if targeting serotonin in the gut can affect mood, the researchers engineered mice to amplify serotonin signaling in the gut — which mimicked an SSRI delivered selectively to the gut. They found that animals with increased serotonin signaling in the gut displayed fewer anxiety and depressive-like behaviors than their unaffected littermates.

“These results suggest that SSRIs produce therapeutic effects by working directly in the gut,” Ansorge says.

The animals also displayed none of the cognitive or gastrointestinal side effects commonly seen in patients taking SSRIs or in mice with increased serotonin signaling throughout their entire bodies.

“Based on what we know about interactions between the brain and gut, we expected to see some effect. But to see enhanced serotonin signaling in the gut epithelium produce such robust antidepressant and anxiety-relieving effects without noticeable side effects was surprising even to us,” Ansorge says.

“There may be an advantage to targeting antidepressants selectively to the gut epithelium,” adds Margolis. “Systemic treatment may not be necessary for eliciting the drugs’ benefits.”

The researchers also found that the vagus nerve was necessary for the gut’s antidepressant and anxiety-relieving effects. The vagus nerve has long been known for its critical role in brain/gut communication, but mostly for top-down communication from the brain to the gut. Here the researchers found the other direction to be critical, with vagus nerve signaling from the gut to the brain.

A better antidepressant option during pregnancy?

SSRI treatment poses challenges in pregnancy, because some studies have found that exposure in utero may negatively affect the development of mood, behavior, and cognition later in childhood. Ansorge’s previous research in animals has found similar results, identifying behavioral changes in offspring exposed only briefly to SSRIs during development.

The new study adds to the evidence that in utero exposure to serotonin-targeting antidepressants has negative effects on children. The researchers looked at more than 400 mothers and babies and found that children exposed to such antidepressants were 3 times more likely to develop constipation in their first year of life.

Ansorge and Margolis caution that pregnant people currently taking SSRIs should not discontinue their treatment based on these and other findings. “Maternal depression and anxiety can have many unwanted effects on fetal and child development and must thus be treated and monitored adequately to the benefit of both mother and child,” says Ansorge.

The researchers are now working to develop a selective SSRI that targets the gut, which could be a better option for treating depression and anxiety especially in pregnant women.

“Our findings indicate that we may be able to treat a mother’s depression or anxiety effectively without exposing the child,” Ansorge says, “and we are working on drug delivery technology that will hopefully help us achieve that.”